Researchers at The University of Texas MD Anderson Cancer Center have developed a novel genome-wide CRISPR screening tool, allowing for significant improvements in the efficacy of chimeric antigen receptor (CAR) natural killer (NK) cell therapies. This groundbreaking study, published on March 15, 2024, in the journal Cancer Cell, reveals how targeted gene editing can enhance the ability of NK cells to combat various cancer types.
New Insights into NK Cell Function
The study, led by Katy Rezvani, MD, PhD, who serves as a professor of Stem Cell Transplantation and Cellular Therapy, emphasizes the potential of the PreCiSE discovery platform. This tool has uncovered critical gene targets that, when edited, significantly improve the antitumor activity of NK cells. Rezvani remarked, “PreCiSE is more than a screening tool. It is a roadmap that reveals how tumors suppress our cells and how to reengineer CAR NK cells to resist those pressures across many cancer types.”
By utilizing PreCiSE, researchers identified multiple checkpoints and pathways that regulate NK cell activity in the tumor microenvironment, which typically suppresses immune responses. The study demonstrated that editing specific gene targets can enhance both innate and CAR-mediated NK cell functions, improve metabolic fitness, boost pro-inflammatory cytokine production, and expand cytotoxic NK cell subsets in cancer models that previously showed resistance to treatment.
Key Gene Targets Identified
Among the three validated targets highlighted in the research are MED12, ARIH2, and CCNC. The significance of the findings extends beyond these individual genes, as PreCiSE offers an unbiased map of NK cell regulators that can be prioritized and combined to design more effective CAR NK cell therapies.
The study validated these targets in vivo using various tumor models and under defined immune-suppressive conditions. Some of the regulators, such as MED12 and CCNC, are known to intersect with pathways recognized in T cell biology, whereas others, including ARIH2, appear to be specific to NK cell functions. This specificity highlights the innovative nature of a platform tailored for NK cells.
Rezvani’s lab has been instrumental in advancing engineered NK cell therapies, taking CAR NK approaches into clinical trials for patients with advanced hematologic and solid malignancies. The current findings are expected to significantly enhance both the efficacy and activity of CAR NK cells across a broader range of cancer types.
The research received generous support from various philanthropic contributions, including major commitments from organizations such as the Marcus Foundation, Inc. and the National Institutes of Health. The team at the Institute for Cell Therapy Discovery & Innovation will continue to build upon these findings to develop impactful therapies for patients in need.
For a full list of collaborating authors and their disclosures, please refer to the published paper.
